Mariana López-Luppo1, Joana Catita1, David Ramos2, Marc Navarro1, Ana Carretero1, Luísa Mendes-Jorge3, Pura Muñoz-Cánoves4, Alfonso Rodriguez-Baeza5, Victor Nacher1, Jesus Ruberte6. 1. Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 2Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain. 2. Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 3Interdisciplinary Centre of Research in Animal Health, Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal. 3. Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 3Interdisciplinary Centre of Research in Animal Health, Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal 4Department of Morphology and Function, Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal. 4. Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. 5. Department of Morphological Sciences, School of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain. 6. Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 2Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain 3Interdisciplinary Centre of Research in Animal Health, Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal.
Abstract
Purpose: Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse. Methods: Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated β-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy. Results: Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age human microaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the β1 subunit of fibronectin receptor α5β1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1-deficient mice presented abundant retinal microaneurysms. Conclusions: Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.
Purpose: Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse. Methods: Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated β-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy. Results: Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age humanmicroaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the β1 subunit of fibronectin receptor α5β1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1-deficient mice presented abundant retinal microaneurysms. Conclusions: Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.
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